Expert Critique

FROM THE ASCO Reading Room

Vinay Gupta, MDOncologySaint Luke's Cancer InstituteKansas City, MO

Therapeutic options for small cell lung cancer are limited. First-line therapy for extensive disease remains platinum-based chemotherapy, and despite a large body of research, there has not been further advancement with chemotherapy. Recent developments, though small incremental gains, in improving outcomes with small cell lung carcinoma have arisen from use of consolidative thoracic radiation. Immunotherapy with combination ipilimumab and nivolumab has shown modest benefit, and in a field bereft of effective second-line therapy, has been adopted in practice. More effective therapies are therefore needed.

This article reviews the role of rovalpituzumab tesirine or Rova-T in the management of small cell lung cancer. Rova-T was tested in a phase I trial with a heavily pre-treated population and showed clinical benefit, and this was more so in patients with increased expression of DLL3 via immunohistochemistry (IHC). The overall response rate was as high as 55% in patient with >50% expression of DLL3 via IHC. A biomarker such as DLL3 could help in identifying patients who are better suited to ROVA-T therapy. However, this needs to be validated in a larger study, and more work needs to be done to bring this agent into clinical practice.

Full Critique

It's an expression that you don't hear that often with regard to small-cell lung cancer (SCLC): cautious optimism. After all, SCLC has a 5-year survival rate of only about 2%, and treatment options haven't progressed much beyond chemotherapy-based agents in the last few decades.

But a dipeptide linker called delta-like protein 3 (DLL3) has gained attention as a potential immunotherapy target for relapsed SCLC. DLL3 "is an inhibitory ligand of the Notch signaling pathway that is normally expressed exclusively on intracellular membranes, including those of the Golgi apparatus," explained Jason Lewis, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and colleagues.

When expressed in SCLC, DLL3 induction results in localization to the cell surface. In non-malignant cells, there is an absence of detectable cell surface DLL3. The protein manifests in this manner in approximately 80% of SCLC tumors -- hence the potential for being a marker for tumor-cell specific therapy, Lewis' group noted.

Another MSKCC clinician, Joshua Sabari, MD, pointed out that high expression of DLL3 in most cases of SCLC has been linked to expression of Achaete-scute homologue 1 (ASCL1), a key transcription factor driving SCLC oncogenesis.

"Exceptionally high clonogenic capacity, early metastatic spread, and rapid tumor repopulation after exposure to chemotherapy are hallmark features of SCLC," Lewis noted.

SCLC researchers have turned a critical eye to DLL3, including early results with an investigational agent designed to exploit SCLC DLL3 expression.

Do You DLL3?

At the 2017 World Conference on Lung Cancer (WCLC) in Yokohama, Japan, Li-Xu Yan, MD, from the Guangdong Academy of Medical Sciences in Guangdong, China, and colleagues stressed that determining if an SCLC patient is even a candidate for DLL3-based immunotherapy is critical to ensuring optimal treatment outcome: "Accurate diagnosis is the premise of accurate treatment. To study the heterogeneity of molecular biomarkers is conducive to better guiding targeted treatments."

Yan's group recruited 335 SCLC patients from 2006 to 2015, and collected biopsy and surgical resection specimens. From these specimens, the team evaluated and determined each specimen's DLL3 expression using an IHC H score.

There were no differences between DLL3 expression on those patients who had paired surgical resection and biopsy specimens. The researchers also found that a high DLL3 expression resulted in lower overall survival (OS) than SCLC patients with a low DLL3 expression, but it did not reach the level of statistical significance.

"The take-home message is that biopsy is a reliable method for evaluating DLL3 expression," said Yan during a WCLC press briefing. "Further evaluation of the scoring system for predicting DLL3-targeted therapeutic efficacy and clinical significance of DLL3 expression is warranted."

Rova-T and SCLC

Therapeutic targets that deliver results in non-small cell lung cancer (NSCLC), such as anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies or programmed cell death 1 ligand 1 (PD-L1) inhibitors, just don't have the same punch in SCLC. In clinical trials, post-chemotherapy SCLC patients have demonstrated OS times of 6 to 8 months with these forms of immunotherapy, pointed out Antonio Rossi, MD, from S.G. Moscati Hospital in Avellino, Italy.

The reason for this lack of success in translating NSCLC immunotherapy targets to SCLC treatment is that the "immune microenvironment of SCLC seems to be distinct from that of other solid tumors, with few tumor-infiltrating lymphocytes and low levels of the immune-checkpoint protein PD-L1," Sabari's group explained.

AbbVie Stemcentrix in San Francisco has developed a first-in-class antibody-drug conjugate to exploit SCLC DLL3 expression called rovalpituzumab tesirine (Rova-T).

The company's in-house researchers utilized patient-derived xenograft (PDX) tumors to test the compound, and reported inducing durable tumor regressions in vivo across multiple PDX models from patients with both limited and extensive-stage disease. The researchers also conducted serial transplantation experiments with a limiting dilution of cells that provided functional evidence confirming the lack of tumor recurrence after Rova-T therapy.

The agent consists of humanized monoclonal antibody against DLL3 and a pyrrolobenzodiazepine (PBD) dimer toxin. PBDs are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. The cytotoxin cannot be given as a standalone treatment, due to its high toxicity; however, when internalized by the cancer cell through the antibody conjugate agent, the toxin is safely released and kills the cancer cell.

"If DLL3 is elevated as a consequence of ASCL1 overexpression, it serves as an excellent surface protein for the ASCL1+ phenotype and can act as a Trojan horse for toxin delivery," Dylla's group said of the mechanism of action for Rova-T.

"Moreover, if DLL3 is in fact a driver of tumorigenesis, its down-regulation to evade [Rova-T] should result in slowed tumor growth due to Notch reactivation."

Results of the phase I study were presented at the 2016 American Society of Clinical Oncology annual meeting. MSKCC researchers evaluated 74 relapsed SCLC patients who received Rova-T at dose levels ranging from 0.05 to 0.8 mg/kg at either every 3 or 6 weeks.

Among the 61 evaluable patients treated at doses of 0.2-0.4 mg/kg, the overall response rate (ORR) was 25%. Of the cohort, 22 patients had ≥50% of cells expressing DLL3 by immunohistochemistry (IHC) from archive tissue specimens showing an ORR of 55% with a median OS of 8 months.

In 10 patients treated in a third-line setting, where no approved therapy currently exists, the ORR was 70%. The most common grade ≥3 adverse events were serosal effusions in 14% of patients, thrombocytopenia in 12%, and skin reactions in 8% of cases.

The authors, including David Spigel, MD, of the Sarah Cannon Research Institute in Nashville, reported in the Lancet Oncology in early 2017 that the maximum tolerated dose of rovalpituzumab tesirine was 0.4 mg/kg every 3 weeks, and that the recommended phase II dose and schedule is 0.3 mg/kg every 6 weeks.

Results from the study led to a single-arm pivotal study (completed in January 2017) in third-line DLL3-expressing SCLC. "What we discovered in this phase I trial is that giving a dose of this medication IV once every 6 weeks, two times, is going to be the recommended schedule of this drug in its phase II and phase III development from here," Spigel said in an interview with VJOncology.

"What was exciting is that in patients with both sensitive and primary resistant refractory/relapsed disease, there were high response rates compared with historical controls."

The study by Lewis' group was supported by the NIH and the Druckenmiller Center for Lung Cancer Research.

The phase I study was funded by AbbVie Stemcentrix, the developer of Rova-T. Some coauthors are company employees; other coauthors disclosed support from the National Cancer Institute and the Central and East European Oncology Group.

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